Significant progress has been made in the development of a live attenuated subgroup A respiratory syncytral virus (RSV) vaccine. The complete nucleotide sequence of five live attenuated RSV vaccine candidates has been completed. A menu of attenuating mutations was assembled from this sequence analysis. A cDNA copy of an incompletely attenuated, cold-passaged (cp) RSV was constructed from which viable cpRSV has been recovered. In clinical studies, a more attenuated derivative of cpRSV, cpts248/404, has been shown to be safe, immunogenic, and phenotypically stable in seronegative infants and young children. However, this candidate vaccine replicates to high titer in these seronegative pediatric subjects. Hence, it is possible that the candidate vaccine might not prove to be sufficiently attenuated as more experience is obtained during clinical studies now in progress. Currently, additional mutations are being introduced into the cDNA of cpRSV with the intent of producing a virus with all of the mutations present in the cpts248/404 mutant. If clinical studies indicate that the cpts248/404 virus is insufficiently attenuated, we will attempt to achieve a higher level of attenuation by introducing one or more additional mutations from our menu of attenuating mutations into cpts248/404. In this way, live attenuated subgroup A RSV vaccine candidates will be generated and then evaluated in humans to identify a set of attenuating mutations that together specify a satisfactory balance between attenuation and immunogenicity. Clinical studies to determine if the subgroup B RSV B1 cp52 and cp23 mutants are satisfactorily attenuated for seronegative humans are planned for this year. This strategy was adopted because two temperature sensitive derivatives of the RSV B1 cp52 proved to be over attenuated for seronegative humans. If a satisfactory subgroup B candidate vaccine strain is identified, clinical studies with a bivalent RSV subgroup A and B vaccine will be initiated in humans. The RSV F glycoprotein epitope recognized by a broadly reactive, highly neutralizing human recombinant monoclonal Fab antibody 19 was identified by sequence analysis of neutralizing monoclonal antibody escape mutants.